This Article Full Text Full Text (PDF) All Versions of this Article: 2007-0331TRv1 38/3/251    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Walmsley, S. R. Articles by Chilvers, E. R. PubMed PubMed Citation Articles by Walmsley, S. R. Articles by Chilvers, E. R.

The HIF/VHL Pathway

From Oxygen Sensing to Innate Immunity

¹ Academic Unit of Respiratory Medicine, School of Medicine and Biomedical Sciences, University of Sheffield, Royal Hallamshire Hospital, Sheffield; and ² Respiratory Medicine Division, Department of Medicine, University of Cambridge School of Clinical Medicine, Addenbrooke's and Papworth Hospitals, Cambridge, United Kingdom

Correspondence and requests for reprints should be addressed to Professor E. R. Chilvers, Respiratory Medicine Division, Department of Medicine, University of Cambridge School of Clinical Medicine, Box 157, Addenbrooke's Hospital, Hills Road, Cambridge CB2 2QQ, UK. E-mail: erc24{at}cam.ac.uk

In aerobic organisms, all cells have the capacity to respond to changes in oxygenation through the stabilization and transcriptional activation of hypoxia-inducible factor (HIF). At sites of tissue injury, oxygen delivery to individual cells may be compromised or insufficient due to increased metabolic demands, and it is to these areas that immune cells, including neutrophils, must migrate and operate effectively. In addition to the role of HIF to regulate the adaptive metabolic and survival responses of these cells at sites of reduced oxygenation, more complex interactions between HIF and pro-inflammatory pathways are now emerging. The mechanisms by which HIF modulates pro-inflammatory myeloid cell lifespan and function remain to be fully characterized, but roles for the oxygen-sensing hydroxylase enzymes through direct hydroxylation of NF-B and its repressor protein IB have been suggested. The ability of HIF to modulate cellular glucose utilization is also thought to be important, with the maintenance of intracellular ATP pools linked to enhanced myeloid cell aggregation, motility, invasiveness, and bacterial killing. Additional non–hypoxia-mediated routes to up-regulate HIF are also now recognized. In this review we describe the role of HIF in the oxygen-sensing response, and the oxygen-dependent and -independent regulation of myeloid cell function and longevity. Understanding these processes and the role they play in regulating innate immune responses within inflamed sites, both hypoxic and normoxic, may offer new opportunities for therapeutic intervention.

Key Words: hypoxia-inducible factor • oxygen • neutrophils

CLINICAL RELEVANCE This review highlights new advances in our understanding of how inflammatory cells sense and respond to changes in oxygen tension and the role played by the ubiquitous transcriptional factor hypoxia-inducible factor.